The objective of this project is to learn more about the natural history of IDD prior to the time of its clinical onset. As current data supports the idea, that the appearance of cytoplasmic islet cell autoantibodies (ICA) in most cases precedes onset of IDD by months and years, the feasibility of utilizing the determination of ICA to identify pre-IDD in first degree relatives of patients with IDD will be examined. Other immunologic factors will also be studied longitudinally in these patients to identify parameters that will provide high risk profiles. It is necessary that such data be obtained if immunosuppressive or other early intervention therapies can be used to prevent IDD, since by the time clinical IDD has appeared, irreparable loss of pancreatic Beta cells has occurred. A minimum of 150 first degree relatives of IDD probands who have ICA but not overt diabetes will be identified from screening 3000 siblings with a proband with IDD, as well as the parents of these individuals. All relatives will be followed annually to learn whether diabetes has been diagnosed, and to obtain a serum sample for later studies should they subsequently develop diabetes. Relatives with ICA and matched relative controls without ICA will be studied biannually (siblings) or annually (parents) for evidence of metabolic deterioration to diabetes. Glucose and insulin responses to oral glucose and/or oral sustacal and to intravenous glucoses will be monitored. Other immunologic factors that may enhance predictability of subsequent IDD, will also be determined in ICA positive relatives and ICA negative control relatives; i.e., HLA-phenotype, HLA haplotype sharing (for siblings), presence of other islet cell antibodies (CF-ICA, ICSA, insulin A), non islet autoantibodies (TMA and PCA), presence of activated T cells (expression of Ia or Tac antigens or transferrin receptors), pertubations of the number of T, B and NK cells and T cell subsets (T suppressor/T helper ratios) using fluorescence activated cell sorting techniques and changes in circulating complement factors. A pilot attempt to utilize nuclear magnetic resonance (NMR) scanning to visualize pancreatic inflammation/edema in pre-IDD will also be made. Finally, the feasibility of utilizing determination of ICA to identify those children from the general population who are destined to develop IDD will be tested.